Folinic Acid

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid (folinic acid). It is an active folate metabolite and an essential coenzyme in nucleic acid synthesis during cytotoxic chemotherapy. It is a racemate in which the L-form (L-5-formyltetrahydrofolate) is the active enantiomer.

Mechanism of Action

• Rescue from folate antagonists: calcium folinate and folate antagonists such as methotrexate share the same membrane carrier protein and compete for transport into cells, which promotes the flow of the antagonist out of them. Calcium folinate also protects cells by replenishing the reduced folate pool: it is a pre-reduced source of tetrahydrofolate, so it bypasses the block caused by the antagonist and supplies the various coenzyme forms of folic acid.
• Modulation of 5-fluorouracil: 5-fluorouracil inhibits thymidylate synthase, a key enzyme in pyrimidine synthesis. Calcium folinate raises the intracellular folate pool, which stabilises the 5-fluorouracil–thymidylate synthase complex and increases the inhibition and the cytotoxic activity.
• Resistance: resistance to methotrexate caused by reduced membrane transport also means resistance to folinic acid rescue, because both use the same transport system.

Pharmacokinetics

• Absorption: after oral dosing the peak plasma level is reached after about 2 hours. Absorption is rapid but saturable above 25 mg; bioavailability is 97% for 25 mg, 75% for 50 mg and 37% for 100 mg. After intramuscular injection of an aqueous solution, systemic availability is comparable to intravenous dosing, with a lower peak level.
• Distribution: the volume of distribution of total folates after an oral dose of 25 mg is 44 L. Peak serum levels of the parent substance occur 10 minutes after intravenous and 28 minutes after intramuscular dosing. The inactive D-isomer is present at a higher concentration than the L-form. Folate concentrates in the liver and cerebrospinal fluid, with distribution to all body tissues.
• Metabolism: the main metabolic product is 5-methyltetrahydrofolic acid, formed mainly in the liver and intestinal mucosa; its peak levels occur at 1.5 hours after intravenous and 2.8 hours after intramuscular dosing. The terminal half-life of total reduced folates is reported as 6.2 hours.
• Elimination: the half-life is 32–35 minutes for the active L-form and 352–485 minutes for the inactive D-form. The terminal half-life of the active metabolite is about 6 hours; 80–90% is excreted in urine (as inactive 5- and 10-formyl-tetrahydrofolates) and 5–8% in faeces.

• Tablets, megaloblastic anaemia: megaloblastic anaemia due to folate deficiency.
• Tablets, folate antagonists: to decrease the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy, and in overdose. In cytotoxic therapy this is commonly called ‘calcium folinate rescue’.
• Solution for injection, folate antagonists: to decrease the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy, and in overdose, in adults and children (‘calcium folinate rescue’).
• Solution for injection, with 5-fluorouracil: in combination with 5-fluorouracil in cytotoxic therapy.

• Hypersensitivity to calcium folinate or to any of the excipients.
• Pernicious anaemia or other megaloblastic anaemias due to vitamin B12 deficiency.
• When it is used with methotrexate or 5-fluorouracil, the contraindications of those medicines also apply (see their SmPCs, including for pregnancy and breastfeeding).

The reactions listed by the two SmPCs are mostly rare. In combination with 5-fluorouracil the safety profile mainly reflects the increased toxicity of 5-fluorouracil and depends on its regimen.

Very common (≥1/10): with 5-fluorouracil (injection): bone marrow failure, including fatal cases; mucositis, including stomatitis and cheilitis, with deaths from mucositis; vomiting and nausea (monthly regimen); diarrhoea with high-grade toxicity and dehydration, leading to hospital admission and even death (weekly regimen).

Common (≥1/100 to <1/10): with 5-fluorouracil (injection): palmar-plantar erythrodysaesthesia.

Uncommon (≥1/1,000 to <1/100): fever after the solution for injection.

Rare (≥1/10,000 to <1/1,000): convulsions and/or syncope (tablets); increased frequency of seizures in epileptic patients; insomnia, agitation and depression after high doses; gastrointestinal disorders after high doses (injection).

Very rare (<1/10,000): allergic reactions, including anaphylactoid and anaphylactic reactions (and anaphylactic shock), and urticaria.

Not known: hypersensitivity, urticaria and pyrexia (tablets); hyperammonaemia (with 5-fluorouracil, injection).

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, some fatal, have been reported in patients given levofolinate (the active L-form of calcium folinate) in combination with other agents known to be associated with these disorders; a contribution of levofolinate cannot be excluded.

• Folic acid antagonists (for example co-trimoxazole, pyrimethamine, methotrexate, antibiotics with an antifolate effect): their effect can be reduced or completely neutralised by calcium folinate if the recommended doses are not respected.
• Antiepileptics (phenobarbital, primidone, phenytoin, succinimides): calcium folinate can weaken their effect and increase the frequency of seizures in epileptic patients, because plasma levels of enzyme-inducing antiepileptics fall when folates increase their liver metabolism as cofactors.
• Chloramphenicol with folic acid: in folate-deficient patients, taking both together can antagonise the haematopoietic response to folic acid.
• 5-Fluorouracil: calcium folinate can increase both the efficacy and the toxicity of 5-fluorouracil.
• Food: the tablets may be taken fasting or after meals, although bioavailability studies were done only after meals.

Calcium folinate is used with methotrexate or 5-fluorouracil only under the direct supervision of a physician experienced in cancer chemotherapy. The tablets are taken by mouth. The solution for injection is given only by intramuscular or intravenous injection and is never given intrathecally.

Tablets (15 mg)

• Megaloblastic anaemia due to folate deficiency: the most common oral treatment is one 15 mg tablet daily, usually for 10–15 days. The maximum dose is 25 mg, because absorption is saturable.
• Methotrexate rescue: the methotrexate protocol sets the rescue regimen. Rescue is necessary when methotrexate doses exceed 500 mg/m² body surface area and should be considered at 100–500 mg/m². It starts 24 hours after the beginning of the intravenous methotrexate infusion; in general 15 mg of folinic acid (about 10 mg/m²) is given every 6 hours for a total of 10 doses.
• Monitoring and support: serum creatinine and methotrexate levels are measured at least once daily. Folinic acid continues until the methotrexate level is below 0.05 µmol/L, with good hydration (3 litres a day) and alkalinisation of the urine to a pH of 7 or above with sodium bicarbonate. Foods, drinks and medicines that increase urinary acidity are avoided.
• Normal methotrexate clearance: the serum level should be under 10 µM at 24 hours, under 1 µM at 48 hours and under 0.1 µM at 72 hours.
• Late delay in clearance (level still above 0.1 µM at 72 hours, or above 0.1 µM at 96 hours): the initial dose is continued at 15 mg every 6 hours until the level is below 0.05 µM.
• Early delay in clearance (level of 10 µM or more at 24 hours or 1 µM or more at 48 hours, or a 100% or greater rise in serum creatinine at 24 hours): intravenous calcium folinate is recommended (see the injection SmPC). It should also be given parenterally if there is gastrointestinal toxicity, nausea or vomiting.
• Antidote to other folate antagonists: for trimetrexate, calcium folinate is given every day during treatment and for 72 hours after the last dose, orally as four doses of 20 mg/m² at equal intervals, adjusted to the haematological toxicity; intravenous folinate is advised for trimetrexate overdose. For trimethoprim toxicity, 7.5 mg daily by mouth after stopping trimethoprim until the blood count is normal. For high-dose or prolonged low-dose pyrimethamine, 7.5 mg to 45 mg daily according to blood counts; because absorption saturates above 25 mg, the parenteral route is advisable in these cases.

Solution for Injection (10 mg/mL)

• Method: intramuscular or intravenous only. No more than 160 mg per minute is injected intravenously, because of the calcium content. For intravenous infusion it can be diluted with sodium chloride 0.9% or glucose 5% solution.
• Methotrexate rescue: rescue must be given parenterally in patients with malabsorption syndromes or other gastrointestinal disorders in whom enteral absorption is not assured; doses above 25–50 mg are given parenterally because enteral absorption is saturable. Rescue is necessary at methotrexate doses above 500 mg/m² and should be considered at 100–500 mg/m². Dose and duration depend mainly on the type and dose of methotrexate therapy, the appearance of toxicity and the individual ability to excrete methotrexate. As a rule, the first dose is 15 mg (6–12 mg/m²), given 12–24 hours (24 hours at most) after the start of the methotrexate infusion, and the same dose is repeated every 6 hours for 72 hours. After several parenteral doses, treatment can switch to the oral form.
• Supportive measures: high urine output and urine alkalinisation, to ensure fast excretion of methotrexate, are an integral part of the rescue, and renal function is monitored with daily serum creatinine. The residual methotrexate level is measured 48 hours after the start of the infusion. If it is 0.5 µmol/L or more, additional calcium folinate is given every 6 hours for 48 hours or until the level is below 0.05 µmol/L: 15 mg/m² at 0.5 µmol/L or more, 100 mg/m² at 1.0 µmol/L or more, and 200 mg/m² at 2.0 µmol/L or more.
• With 5-fluorouracil: different regimens and doses are used, and none has been shown to be best. The SmPC gives these examples from the treatment of advanced or metastatic colorectal cancer in adults and elderly patients (there are no data in children):
  • Twice-monthly: 200 mg/m² by intravenous infusion over 2 hours, with a 5-fluorouracil bolus of 400 mg/m² and a 22-hour infusion of 5-fluorouracil (600 mg/m²) on 2 consecutive days, every 2 weeks on days 1 and 2 (see the SmPC for the order of administration).
  • Weekly: 20 mg/m² as an intravenous bolus, or 200–500 mg/m² by intravenous infusion over 2 hours, followed by 5-fluorouracil 500 mg/m² as a bolus in the middle or at the end of the infusion.
  • Monthly: 20 mg/m² as an intravenous bolus, or 200–500 mg/m² by infusion over 2 hours, followed by 5-fluorouracil 425 or 370 mg/m² as a bolus on 5 consecutive days.
  • The dose of 5-fluorouracil and the treatment-free interval may need adjusting to the patient’s condition, response and dose-limiting toxicity; the calcium folinate dose does not need to be reduced. The number of cycles is left to the physician.
• Antidote to other folate antagonists: for trimetrexate, 20 mg/m² intravenously over 5–10 minutes every 6 hours (80 mg/m² a day), or orally as four doses of 20 mg/m² at equal intervals, during treatment and for 72 hours after the last dose; for trimetrexate overdose (possibly above 90 mg/m² without calcium folinate), 40 mg/m² intravenously every 6 hours for 3 days after stopping trimetrexate. For trimethoprim, 3–10 mg a day intravenously until the blood count recovers. For pyrimethamine, 5–50 mg a day alongside it, based on peripheral blood counts.

Special Populations

• Renal impairment: pre-existing or methotrexate-induced renal impairment can delay methotrexate excretion and may increase the need for higher doses or longer use of calcium folinate.
• Children: the injection is indicated for methotrexate rescue and overdose in adults and children; there are no data on its use with 5-fluorouracil in children.

No Intrathecal Use

The solution for injection must be given only by intramuscular or intravenous injection and must not be given intrathecally. Deaths have occurred when folinic acid was given intrathecally after an intrathecal overdose of methotrexate.

Supervision and Anaemia

• Calcium folinate may be used with methotrexate (and, for the injection, with 5-fluorouracil) only under the direct supervision of a physician experienced in cancer chemotherapy.
• It may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.
• Many cytotoxic medicines that inhibit DNA synthesis, directly or indirectly (hydroxycarbamide, cytarabine, mercaptopurine, tioguanine), cause macrocytosis. This macrocytosis must not be treated with folinic acid.

Epilepsy

In epileptic patients treated with phenobarbital, phenytoin, primidone or succinimides, seizures may become more frequent because plasma levels of the antiepileptic fall. Clinical monitoring, possibly monitoring of plasma concentrations and, if needed, adjustment of the antiepileptic dose are recommended during calcium folinate treatment and after it is stopped.

Methotrexate Rescue

• Calcium folinate has no effect on the non-haematological toxicity of methotrexate, such as kidney damage or precipitation of the metabolite in the kidney. Patients with delayed methotrexate elimination can develop reversible kidney failure and other methotrexate-related toxicities.
• Excessive doses of calcium folinate should be avoided because they can impair the antitumour activity of methotrexate, especially in tumours of the central nervous system, where calcium folinate accumulates after repeated treatment.
• An accidental overdose of a folate antagonist such as methotrexate is a medical emergency. The longer the interval between methotrexate and calcium folinate rescue, the less effective calcium folinate is at counteracting the toxicity.
• Serum creatinine and methotrexate are monitored at least once daily, and urine pH is kept at 7.0 or above in methotrexate overdose or delayed excretion. If laboratory abnormalities or clinical toxicity appear, the possibility that the patient takes other medicines that interact with methotrexate (for example by interfering with its elimination or albumin binding) is considered.

Combination with 5-Fluorouracil

• Calcium folinate can increase the toxicity of 5-fluorouracil, particularly in elderly and debilitated patients. The most frequent signs are leucopenia, mucositis, stomatitis and/or diarrhoea, which may limit the dose. If toxicity occurs in the combination, the 5-fluorouracil dose must be reduced more than it would be for 5-fluorouracil alone.
• The combination is not started or continued in patients with symptoms of gastrointestinal toxicity, whatever their severity, until all symptoms have completely resolved.
• Diarrhoea can signal gastrointestinal toxicity and rapid clinical deterioration leading to death. Patients with diarrhoea are monitored carefully until it has completely gone, and with diarrhoea and/or stomatitis the 5-fluorouracil dose is reduced until the symptoms have completely disappeared.
• A reduced starting dose of 5-fluorouracil is recommended in elderly patients and in those who have had earlier radiotherapy.
• Calcium folinate must not be mixed with 5-fluorouracil in the same intravenous injection or infusion. Calcium levels are monitored, and calcium is given if they are low.

Pregnancy, Breastfeeding and Fertility

The statements below come from the tablet SmPC. The injection SmPC refers to the SmPCs of methotrexate and 5-fluorouracil for their use in pregnancy and breastfeeding.

• Pregnancy: there are no adequate, well-controlled studies in pregnant women, and animal studies are insufficient for reproductive toxicity; there is no indication that folic acid causes harm in pregnancy. Methotrexate should be given in pregnancy only for strict indications, weighing benefit to the mother against risk to the foetus. If methotrexate or another folate antagonist must be given in pregnancy or breastfeeding, there are no limits on using calcium folinate to reduce the toxicity or counteract the effects. The SmPCs of those medicines should be consulted.
• Breastfeeding: it is unknown whether calcium folinate passes into human milk. It can be used during breastfeeding when needed for the therapeutic indications.
• Fertility: calcium folinate is an intermediate in folic acid metabolism and occurs naturally in the body. No animal fertility studies have been done.

Excipients

• Lactose (tablets): each tablet contains 114 mg of lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. The tablets contain less than 1 mmol (23 mg) of sodium, that is, they are essentially sodium-free.
• Sodium (injection): each mL contains 0.14 mmol (3.22 mg) of sodium. A 5 mL vial contains less than 1 mmol (23 mg), a 10 mL vial 32.2 mg, a 20 mL vial 64.4 mg, a 30 mL vial 96.6 mg and a 50 mL vial 161 mg of sodium.

Effect on Driving

There is no evidence that calcium folinate affects the ability to drive or use machines (tablet SmPC).

• Tablets: do not store above 30 °C. They come in PVC/aluminium blisters, in packs of 10.
• Solution for injection: store in a refrigerator at 2–8 °C, in the original package, and handle it as a cold-chain product. Do not use it after the expiry date. For storage after dilution, see Shelf Life.

• Tablets: 2 years.
• Solution for injection: 2 years in unopened vials. The vial is for a single use, and any solution left over is discarded immediately after first use. Diluted with sodium chloride 0.9% or glucose 5% infusion solution, the diluted solution was physically and chemically stable for 72 hours at room temperature (below 25 °C). From a microbiological point of view it is used immediately after dilution; the SmPC gives further in-use conditions.

Prescription only (Rx). When used with methotrexate or 5-fluorouracil, it is used only under the direct supervision of a physician experienced in cancer chemotherapy. The 15 mg tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription. The solution for injection is given by intramuscular or intravenous injection by healthcare staff, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C. It must never be given intrathecally.